Researcher in the lab

Credit: Rhoda Baer

Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.

Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.

And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.

“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.

To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.

As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.

Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.

In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.

The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.

Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.

When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.

The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.

Researcher in the lab

Credit: Rhoda Baer

Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.

Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.

And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.

“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.

To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.

As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.

Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.

In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.

The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.

Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.

When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.

The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.

Researcher in the lab

Credit: Rhoda Baer

Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.

Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.

And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.

“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.

To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.

As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.

Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.

In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.

The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.

Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.

When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.

The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.

Credit: National Institute

of General Medical Sciences

There are significant challenges to overcome before whole-genome sequencing can be routinely used in the clinic, researchers have reported in JAMA.

In sequencing the entire genome of 12 healthy individuals, the team found they sometimes had difficulty identifying

variants in disease-associated genes, disagreed about which variants were particularly important for disease, and were uncertain about clinically reportable findings.

The research also revealed that detailed genome analysis required up to 100 hours of manual assessment per person, and the total cost of this process (including follow-up tests) could exceed $15,000 per person.

This is more expensive and labor-intensive than previous estimates, the researchers noted.

“We need to be very honest about what we can and cannot do at this point in time,” said study author Euan Ashley, MB ChB, DPhil, of Stanford University in California.

“Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.”

To identify these hurdles, Dr Ashley and his colleagues evaluated whole-genome sequencing in 12 healthy individuals. The team took note of the degree of sequencing accuracy necessary to make clinical decisions, the time it took to manually analyze each person’s results, and the costs involved.

The researchers discovered that sequencing could not provide reliable results regarding all inherited disease genes or consistently detect variants with the highest potential clinical effects.

Depending on the sequencing platform used, 10% to 19% of inherited disease genes were not covered to accepted standards for single-nucleotide variant discovery.

And although genotype concordance was high for previously described single-nucleotide variants—99% to 100%—it was low for small insertions and deletions—53% to 59%.

“It’s ironic, and slightly sobering, that we struggle the most in identifying insertions and deletions—those changes in the genome that are most impactful,” Dr Ashley said.

Nevertheless, he and his colleagues were able to identify an average of about 100 variants per person that were considered important enough for follow-up. Each variant required about an hour of investigation to assess the relevant scientific literature and determine whether the change was likely to modify disease risk in the individual.

After this process, the researchers were left with approximately 2 to 6 results they felt could be clinically important.

The variants expected to have potential health consequences were shared with 3 primary care physicians and 2 medical geneticists, who independently studied the results and recommended possible follow-up tests for each person.

The researchers estimated that the median cost for sequencing and variant interpretation was $14,815 (range, $14,050 to $15,715), plus the costs of computing infrastructure and data storage. And the projected costs for follow-up tests ranged from $351 to $776.

Despite the challenges they identified, the team said they are confident that whole-genome sequencing is worth pursuing.

“Our intention in doing this analysis was to draw a line describing where we are with this technology at this point in time and identify how best to move forward,” Dr Ashley said. “Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized.”

Credit: National Institute

of General Medical Sciences

There are significant challenges to overcome before whole-genome sequencing can be routinely used in the clinic, researchers have reported in JAMA.

In sequencing the entire genome of 12 healthy individuals, the team found they sometimes had difficulty identifying

variants in disease-associated genes, disagreed about which variants were particularly important for disease, and were uncertain about clinically reportable findings.

The research also revealed that detailed genome analysis required up to 100 hours of manual assessment per person, and the total cost of this process (including follow-up tests) could exceed $15,000 per person.

This is more expensive and labor-intensive than previous estimates, the researchers noted.

“We need to be very honest about what we can and cannot do at this point in time,” said study author Euan Ashley, MB ChB, DPhil, of Stanford University in California.

“Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.”

To identify these hurdles, Dr Ashley and his colleagues evaluated whole-genome sequencing in 12 healthy individuals. The team took note of the degree of sequencing accuracy necessary to make clinical decisions, the time it took to manually analyze each person’s results, and the costs involved.

The researchers discovered that sequencing could not provide reliable results regarding all inherited disease genes or consistently detect variants with the highest potential clinical effects.

Depending on the sequencing platform used, 10% to 19% of inherited disease genes were not covered to accepted standards for single-nucleotide variant discovery.

And although genotype concordance was high for previously described single-nucleotide variants—99% to 100%—it was low for small insertions and deletions—53% to 59%.

“It’s ironic, and slightly sobering, that we struggle the most in identifying insertions and deletions—those changes in the genome that are most impactful,” Dr Ashley said.

Nevertheless, he and his colleagues were able to identify an average of about 100 variants per person that were considered important enough for follow-up. Each variant required about an hour of investigation to assess the relevant scientific literature and determine whether the change was likely to modify disease risk in the individual.

After this process, the researchers were left with approximately 2 to 6 results they felt could be clinically important.

The variants expected to have potential health consequences were shared with 3 primary care physicians and 2 medical geneticists, who independently studied the results and recommended possible follow-up tests for each person.

The researchers estimated that the median cost for sequencing and variant interpretation was $14,815 (range, $14,050 to $15,715), plus the costs of computing infrastructure and data storage. And the projected costs for follow-up tests ranged from $351 to $776.

Despite the challenges they identified, the team said they are confident that whole-genome sequencing is worth pursuing.

“Our intention in doing this analysis was to draw a line describing where we are with this technology at this point in time and identify how best to move forward,” Dr Ashley said. “Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized.”

Credit: National Institute

of General Medical Sciences

There are significant challenges to overcome before whole-genome sequencing can be routinely used in the clinic, researchers have reported in JAMA.

In sequencing the entire genome of 12 healthy individuals, the team found they sometimes had difficulty identifying

variants in disease-associated genes, disagreed about which variants were particularly important for disease, and were uncertain about clinically reportable findings.

The research also revealed that detailed genome analysis required up to 100 hours of manual assessment per person, and the total cost of this process (including follow-up tests) could exceed $15,000 per person.

This is more expensive and labor-intensive than previous estimates, the researchers noted.

“We need to be very honest about what we can and cannot do at this point in time,” said study author Euan Ashley, MB ChB, DPhil, of Stanford University in California.

“Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.”

To identify these hurdles, Dr Ashley and his colleagues evaluated whole-genome sequencing in 12 healthy individuals. The team took note of the degree of sequencing accuracy necessary to make clinical decisions, the time it took to manually analyze each person’s results, and the costs involved.

The researchers discovered that sequencing could not provide reliable results regarding all inherited disease genes or consistently detect variants with the highest potential clinical effects.

Depending on the sequencing platform used, 10% to 19% of inherited disease genes were not covered to accepted standards for single-nucleotide variant discovery.

And although genotype concordance was high for previously described single-nucleotide variants—99% to 100%—it was low for small insertions and deletions—53% to 59%.

“It’s ironic, and slightly sobering, that we struggle the most in identifying insertions and deletions—those changes in the genome that are most impactful,” Dr Ashley said.

Nevertheless, he and his colleagues were able to identify an average of about 100 variants per person that were considered important enough for follow-up. Each variant required about an hour of investigation to assess the relevant scientific literature and determine whether the change was likely to modify disease risk in the individual.

After this process, the researchers were left with approximately 2 to 6 results they felt could be clinically important.

The variants expected to have potential health consequences were shared with 3 primary care physicians and 2 medical geneticists, who independently studied the results and recommended possible follow-up tests for each person.

The researchers estimated that the median cost for sequencing and variant interpretation was $14,815 (range, $14,050 to $15,715), plus the costs of computing infrastructure and data storage. And the projected costs for follow-up tests ranged from $351 to $776.

Despite the challenges they identified, the team said they are confident that whole-genome sequencing is worth pursuing.

“Our intention in doing this analysis was to draw a line describing where we are with this technology at this point in time and identify how best to move forward,” Dr Ashley said. “Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized.”

An adnexal mass is a common gynecological presentation that can affect women of all ages. Typically, the mass is identified during an annual pelvic exam or incidentally when patients undergo pelvic imaging for evaluation of gastrointestinal or gynecological complaints.

The main goal of evaluating an adnexal mass in the nonacute setting is to rule out malignancy. A careful evaluation is needed to accurately distinguish benign from malignant masses, but often a definitive diagnosis only can be achieved with surgery. Hence, in the United States, women have a 5%-10% chance of undergoing surgery to evaluate a mass, but only 13%-21% of these patients are diagnosed with an ovarian cancer (Obstet. Gynecol. 2007;110:201-14).

We will review a stepwise approach for the evaluation of a newly diagnosed mass. As part of our review, we will discuss imaging findings that should prompt surgical evaluation or continued observation, as well as the correct use of the currently available serum biomarkers.

The majority of adnexal masses are benign and present most commonly in premenopausal women. However, in the outpatient setting, the evaluation approach should be aimed at ruling out malignancy regardless of age or reproductive status. The patient’s age should be considered clinically, as the suspicion for ovarian cancer should be heightened in postmenopausal women.

The evaluation should start with a detailed history because it may help in determining the etiology of the mass. Pelvic pain and pressure are very common but nonspecific symptoms in women with adnexal masses. However, if the pain is of sudden onset, urgent evaluation is warranted to rule out adnexal torsion or a ruptured hemorrhagic cyst. A history of dysmenorrhea and/or dyspareunia may suggest endometriosis and coexisting endometrioma, whereas a patient with fever and a vaginal discharge should be evaluated for a tubo-ovarian abscess.

Patients also should be asked about symptoms associated with ovarian cancer including early satiety, constipation, and bloating, as well as their duration. In addition, abnormal uterine bleeding or virilization may suggest the presence of estrogen- or testosterone-secreting tumors. Lastly, a detailed family history is important, as the presence of ovarian, breast, or colon cancer in the family would increase suspicion for hereditary ovarian cancer syndromes.

A thorough physical exam should include a speculum exam as well as bimanual and rectovaginal exams. The focus of the pelvic exam should be determining the size, mobility, and consistency of the mass, as well as other findings that may help discriminate benign versus malignant neoplasms. Malignant masses are usually solid, irregular in shape, and tend to be fixed. Nodularity in the posterior cul-de-sac also is associated with malignancy. The abdominal exam should focus on the presence or absence of ascites (fluid wave), an omental mass, or inguinal adenopathy. However, none of the findings on exam are specific for an ovarian or fallopian tube malignancy, and imaging should be obtained for further evaluation.

Ultrasound is the imaging study of choice for the evaluation of an adnexal mass because it is less expensive than and diagnostically equivalent to other imaging modalities. A pelvic ultrasound can help delineate the anatomic origin of the mass, but it also can detect characteristics of the mass that may help with the diagnosis, and the decision of whether or not to proceed to surgery. Endometriomas, mature teratomas (dermoid cysts), simple ovarian cysts, and hemorrhagic cysts have sonographic features that are highly predictive of the histology. Depending on whether or not the patient is symptomatic, the patient’s age, and comorbidities, these masses might be followed expectantly.

Ultrasound features that are suggestive of malignancy include solid components, septations greater than 2-3 mm, and vascular flow. The presence of ascites or peritoneal nodules detected at the time of ultrasound also is highly suspicious of malignancy in patients with a pelvic mass. If a pelvic ultrasound is equivocal, pelvic magnetic resonance imaging (MRI) is the second study of choice. Computed tomography (CT scan) should be used to evaluate for metastatic disease in patients with suspected ovarian carcinoma (ascites, adenopathy, peritoneal thickening or nodularity, omental thickening).

Serum biomarkers also may aid in the evaluation. The most well-studied and commonly used biomarker in the evaluation of an adnexal mass is CA-125. In general, the utility of CA-125 is limited mainly because of its low specificity, especially in premenopausal women. However, it can be used as adjunct when an ovarian malignancy is suspected based on the patient’s history, risk factors, and imaging findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) advise referral to a gynecologic oncologist for postmenopausal women with an elevated CA-125. Meanwhile, for premenopausal women, the recommendation is for referral of those with a "very elevated" CA-125. However, a specific value has not been established (Obstet. Gynecol. 2011;117:742-6).

CA-125 by itself should not be used to decide whether or not to take a patient to surgery. Nevertheless, once the decision to operate has been made, CA-125 can be used in conjunction with HE4 to calculate a Risk of Malignancy Algorithm (ROMA) score. The score is based on menopausal status, and if the calculated risk is elevated, patient referral to a gynecologic oncologist for her surgery should be strongly considered.

Similarly, the OVA1 test is currently approved by the Food and Drug Administration to assess the likelihood of malignancy in patients who are having surgery for an adnexal mass. The test is also based on menopausal status, and if elevated, a referral to a gynecologic oncologist is recommended. In young women with adnexal masses, germ cell tumor markers may be more helpful (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), while in patients with signs or symptoms of estrogen or androgen excess, sex cord-stromal tumor markers (inhibin B, anti-Müllerian hormone [AMH], testosterone, dehydroepiandrosterone [DHEA], estradiol) would be appropriate to obtain. While no tumor marker is "diagnostic," the results may assist in the decision to perform surgery and consider referral to a gynecologic oncologist.

In summary, the workup for an adnexal mass should include a detailed medical and family history, a thorough physical exam, and imaging with pelvic ultrasound. For premenopausal women, there is a higher incidence of adnexal masses, and, in fact, most of them are benign. In these women, one must weigh the risk/benefit of close monitoring with pelvic ultrasound versus surgical intervention. A serum CA-125 can be helpful, but only if it is significantly elevated.

If uncertainty remains after a complete evaluation has been performed, it is appropriate to refer to a gynecologic oncologist. In postmenopausal women, serum biomarkers should be used in conjunction with the history, physical, and ultrasound because of the higher risk of malignancy. In addition, surgical intervention should be offered to these patients regardless of serum marker values in the setting of a complex mass. If there is high suspicion for malignancy by history and imaging or elevated ROMA or OVA1, referral to a gynecologic oncologist is prudent.

Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at [email protected].

An adnexal mass is a common gynecological presentation that can affect women of all ages. Typically, the mass is identified during an annual pelvic exam or incidentally when patients undergo pelvic imaging for evaluation of gastrointestinal or gynecological complaints.

The main goal of evaluating an adnexal mass in the nonacute setting is to rule out malignancy. A careful evaluation is needed to accurately distinguish benign from malignant masses, but often a definitive diagnosis only can be achieved with surgery. Hence, in the United States, women have a 5%-10% chance of undergoing surgery to evaluate a mass, but only 13%-21% of these patients are diagnosed with an ovarian cancer (Obstet. Gynecol. 2007;110:201-14).

We will review a stepwise approach for the evaluation of a newly diagnosed mass. As part of our review, we will discuss imaging findings that should prompt surgical evaluation or continued observation, as well as the correct use of the currently available serum biomarkers.

The majority of adnexal masses are benign and present most commonly in premenopausal women. However, in the outpatient setting, the evaluation approach should be aimed at ruling out malignancy regardless of age or reproductive status. The patient’s age should be considered clinically, as the suspicion for ovarian cancer should be heightened in postmenopausal women.

The evaluation should start with a detailed history because it may help in determining the etiology of the mass. Pelvic pain and pressure are very common but nonspecific symptoms in women with adnexal masses. However, if the pain is of sudden onset, urgent evaluation is warranted to rule out adnexal torsion or a ruptured hemorrhagic cyst. A history of dysmenorrhea and/or dyspareunia may suggest endometriosis and coexisting endometrioma, whereas a patient with fever and a vaginal discharge should be evaluated for a tubo-ovarian abscess.

Patients also should be asked about symptoms associated with ovarian cancer including early satiety, constipation, and bloating, as well as their duration. In addition, abnormal uterine bleeding or virilization may suggest the presence of estrogen- or testosterone-secreting tumors. Lastly, a detailed family history is important, as the presence of ovarian, breast, or colon cancer in the family would increase suspicion for hereditary ovarian cancer syndromes.

A thorough physical exam should include a speculum exam as well as bimanual and rectovaginal exams. The focus of the pelvic exam should be determining the size, mobility, and consistency of the mass, as well as other findings that may help discriminate benign versus malignant neoplasms. Malignant masses are usually solid, irregular in shape, and tend to be fixed. Nodularity in the posterior cul-de-sac also is associated with malignancy. The abdominal exam should focus on the presence or absence of ascites (fluid wave), an omental mass, or inguinal adenopathy. However, none of the findings on exam are specific for an ovarian or fallopian tube malignancy, and imaging should be obtained for further evaluation.

Ultrasound is the imaging study of choice for the evaluation of an adnexal mass because it is less expensive than and diagnostically equivalent to other imaging modalities. A pelvic ultrasound can help delineate the anatomic origin of the mass, but it also can detect characteristics of the mass that may help with the diagnosis, and the decision of whether or not to proceed to surgery. Endometriomas, mature teratomas (dermoid cysts), simple ovarian cysts, and hemorrhagic cysts have sonographic features that are highly predictive of the histology. Depending on whether or not the patient is symptomatic, the patient’s age, and comorbidities, these masses might be followed expectantly.

Ultrasound features that are suggestive of malignancy include solid components, septations greater than 2-3 mm, and vascular flow. The presence of ascites or peritoneal nodules detected at the time of ultrasound also is highly suspicious of malignancy in patients with a pelvic mass. If a pelvic ultrasound is equivocal, pelvic magnetic resonance imaging (MRI) is the second study of choice. Computed tomography (CT scan) should be used to evaluate for metastatic disease in patients with suspected ovarian carcinoma (ascites, adenopathy, peritoneal thickening or nodularity, omental thickening).

Serum biomarkers also may aid in the evaluation. The most well-studied and commonly used biomarker in the evaluation of an adnexal mass is CA-125. In general, the utility of CA-125 is limited mainly because of its low specificity, especially in premenopausal women. However, it can be used as adjunct when an ovarian malignancy is suspected based on the patient’s history, risk factors, and imaging findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) advise referral to a gynecologic oncologist for postmenopausal women with an elevated CA-125. Meanwhile, for premenopausal women, the recommendation is for referral of those with a "very elevated" CA-125. However, a specific value has not been established (Obstet. Gynecol. 2011;117:742-6).

CA-125 by itself should not be used to decide whether or not to take a patient to surgery. Nevertheless, once the decision to operate has been made, CA-125 can be used in conjunction with HE4 to calculate a Risk of Malignancy Algorithm (ROMA) score. The score is based on menopausal status, and if the calculated risk is elevated, patient referral to a gynecologic oncologist for her surgery should be strongly considered.

Similarly, the OVA1 test is currently approved by the Food and Drug Administration to assess the likelihood of malignancy in patients who are having surgery for an adnexal mass. The test is also based on menopausal status, and if elevated, a referral to a gynecologic oncologist is recommended. In young women with adnexal masses, germ cell tumor markers may be more helpful (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), while in patients with signs or symptoms of estrogen or androgen excess, sex cord-stromal tumor markers (inhibin B, anti-Müllerian hormone [AMH], testosterone, dehydroepiandrosterone [DHEA], estradiol) would be appropriate to obtain. While no tumor marker is "diagnostic," the results may assist in the decision to perform surgery and consider referral to a gynecologic oncologist.

In summary, the workup for an adnexal mass should include a detailed medical and family history, a thorough physical exam, and imaging with pelvic ultrasound. For premenopausal women, there is a higher incidence of adnexal masses, and, in fact, most of them are benign. In these women, one must weigh the risk/benefit of close monitoring with pelvic ultrasound versus surgical intervention. A serum CA-125 can be helpful, but only if it is significantly elevated.

If uncertainty remains after a complete evaluation has been performed, it is appropriate to refer to a gynecologic oncologist. In postmenopausal women, serum biomarkers should be used in conjunction with the history, physical, and ultrasound because of the higher risk of malignancy. In addition, surgical intervention should be offered to these patients regardless of serum marker values in the setting of a complex mass. If there is high suspicion for malignancy by history and imaging or elevated ROMA or OVA1, referral to a gynecologic oncologist is prudent.

Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at [email protected].

An adnexal mass is a common gynecological presentation that can affect women of all ages. Typically, the mass is identified during an annual pelvic exam or incidentally when patients undergo pelvic imaging for evaluation of gastrointestinal or gynecological complaints.

The main goal of evaluating an adnexal mass in the nonacute setting is to rule out malignancy. A careful evaluation is needed to accurately distinguish benign from malignant masses, but often a definitive diagnosis only can be achieved with surgery. Hence, in the United States, women have a 5%-10% chance of undergoing surgery to evaluate a mass, but only 13%-21% of these patients are diagnosed with an ovarian cancer (Obstet. Gynecol. 2007;110:201-14).

We will review a stepwise approach for the evaluation of a newly diagnosed mass. As part of our review, we will discuss imaging findings that should prompt surgical evaluation or continued observation, as well as the correct use of the currently available serum biomarkers.

The majority of adnexal masses are benign and present most commonly in premenopausal women. However, in the outpatient setting, the evaluation approach should be aimed at ruling out malignancy regardless of age or reproductive status. The patient’s age should be considered clinically, as the suspicion for ovarian cancer should be heightened in postmenopausal women.

The evaluation should start with a detailed history because it may help in determining the etiology of the mass. Pelvic pain and pressure are very common but nonspecific symptoms in women with adnexal masses. However, if the pain is of sudden onset, urgent evaluation is warranted to rule out adnexal torsion or a ruptured hemorrhagic cyst. A history of dysmenorrhea and/or dyspareunia may suggest endometriosis and coexisting endometrioma, whereas a patient with fever and a vaginal discharge should be evaluated for a tubo-ovarian abscess.

Patients also should be asked about symptoms associated with ovarian cancer including early satiety, constipation, and bloating, as well as their duration. In addition, abnormal uterine bleeding or virilization may suggest the presence of estrogen- or testosterone-secreting tumors. Lastly, a detailed family history is important, as the presence of ovarian, breast, or colon cancer in the family would increase suspicion for hereditary ovarian cancer syndromes.

A thorough physical exam should include a speculum exam as well as bimanual and rectovaginal exams. The focus of the pelvic exam should be determining the size, mobility, and consistency of the mass, as well as other findings that may help discriminate benign versus malignant neoplasms. Malignant masses are usually solid, irregular in shape, and tend to be fixed. Nodularity in the posterior cul-de-sac also is associated with malignancy. The abdominal exam should focus on the presence or absence of ascites (fluid wave), an omental mass, or inguinal adenopathy. However, none of the findings on exam are specific for an ovarian or fallopian tube malignancy, and imaging should be obtained for further evaluation.

Ultrasound is the imaging study of choice for the evaluation of an adnexal mass because it is less expensive than and diagnostically equivalent to other imaging modalities. A pelvic ultrasound can help delineate the anatomic origin of the mass, but it also can detect characteristics of the mass that may help with the diagnosis, and the decision of whether or not to proceed to surgery. Endometriomas, mature teratomas (dermoid cysts), simple ovarian cysts, and hemorrhagic cysts have sonographic features that are highly predictive of the histology. Depending on whether or not the patient is symptomatic, the patient’s age, and comorbidities, these masses might be followed expectantly.

Ultrasound features that are suggestive of malignancy include solid components, septations greater than 2-3 mm, and vascular flow. The presence of ascites or peritoneal nodules detected at the time of ultrasound also is highly suspicious of malignancy in patients with a pelvic mass. If a pelvic ultrasound is equivocal, pelvic magnetic resonance imaging (MRI) is the second study of choice. Computed tomography (CT scan) should be used to evaluate for metastatic disease in patients with suspected ovarian carcinoma (ascites, adenopathy, peritoneal thickening or nodularity, omental thickening).

Serum biomarkers also may aid in the evaluation. The most well-studied and commonly used biomarker in the evaluation of an adnexal mass is CA-125. In general, the utility of CA-125 is limited mainly because of its low specificity, especially in premenopausal women. However, it can be used as adjunct when an ovarian malignancy is suspected based on the patient’s history, risk factors, and imaging findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) advise referral to a gynecologic oncologist for postmenopausal women with an elevated CA-125. Meanwhile, for premenopausal women, the recommendation is for referral of those with a "very elevated" CA-125. However, a specific value has not been established (Obstet. Gynecol. 2011;117:742-6).

CA-125 by itself should not be used to decide whether or not to take a patient to surgery. Nevertheless, once the decision to operate has been made, CA-125 can be used in conjunction with HE4 to calculate a Risk of Malignancy Algorithm (ROMA) score. The score is based on menopausal status, and if the calculated risk is elevated, patient referral to a gynecologic oncologist for her surgery should be strongly considered.

Similarly, the OVA1 test is currently approved by the Food and Drug Administration to assess the likelihood of malignancy in patients who are having surgery for an adnexal mass. The test is also based on menopausal status, and if elevated, a referral to a gynecologic oncologist is recommended. In young women with adnexal masses, germ cell tumor markers may be more helpful (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), while in patients with signs or symptoms of estrogen or androgen excess, sex cord-stromal tumor markers (inhibin B, anti-Müllerian hormone [AMH], testosterone, dehydroepiandrosterone [DHEA], estradiol) would be appropriate to obtain. While no tumor marker is "diagnostic," the results may assist in the decision to perform surgery and consider referral to a gynecologic oncologist.

In summary, the workup for an adnexal mass should include a detailed medical and family history, a thorough physical exam, and imaging with pelvic ultrasound. For premenopausal women, there is a higher incidence of adnexal masses, and, in fact, most of them are benign. In these women, one must weigh the risk/benefit of close monitoring with pelvic ultrasound versus surgical intervention. A serum CA-125 can be helpful, but only if it is significantly elevated.

If uncertainty remains after a complete evaluation has been performed, it is appropriate to refer to a gynecologic oncologist. In postmenopausal women, serum biomarkers should be used in conjunction with the history, physical, and ultrasound because of the higher risk of malignancy. In addition, surgical intervention should be offered to these patients regardless of serum marker values in the setting of a complex mass. If there is high suspicion for malignancy by history and imaging or elevated ROMA or OVA1, referral to a gynecologic oncologist is prudent.

Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at [email protected].

An Institute of Medicine committee could not reach consensus on a single definition of Gulf War illness and recommended in a new report that clinicians and researchers at least narrow it down to two definitions.

That’s the preferred term – Gulf War illness – for a slew of health problems that occur at a higher rate in the approximately 697,000 U.S. veterans who served in the 1990-1991 Gulf War than in other veterans, the committee said. Gulf War illness is widely used and is more accurate than other terms used over the years for the same problems, including Gulf War syndrome, chronic multisystem illness, unexplained illness, medically unexplained symptoms, and medically unexplained physical symptoms, the report stated.

The Institute of Medicine (IOM) drafted a committee of 16 experts at the request of the Department of Veterans Affairs to try to develop a case definition for what's now called Gulf War illness in order to help standardize diagnosis, inclusion in research studies, and treatments. The committee's 120-page report, "Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined," is available on the IOM website.

Unable to find validation for one definition because of methodologic limitations in the studies, the committee recommended using either a broader definition from the Centers for Disease Control and Prevention (CDC) or a more restrictive one from studies of Kansas veterans, depending on the situation. Between the two of them, the definitions capture the most common symptoms of Gulf War illness and provide a framework for more focused research and treatment, the report said.

The committee found 2,033 articles in the literature focused on Gulf War illness symptoms and closely reviewed 718 of them. It found no objective diagnostic criteria but saw cumulative evidence that Gulf War illness is real. Fatigue, pain, and neurocognitive, gastrointestinal, respiratory, and/or dermatologic symptoms were reported with higher frequency in Gulf War veterans than in veterans of the same era who had not been deployed or were deployed elsewhere.

To identify the illness in a Gulf War veteran, the CDC definition requires one or more symptoms in at least two of the following categories: fatigue, pain, or mood and cognition. The Kansas definition requires symptoms in at least three of the following domains: fatigue or sleep, pain, neurologic or cognitive or mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms.

The CDC definition identified the illness in 29%-60% of Gulf War veterans, depending on the population studied. The Kansas definition identified the illness in 34% of Kansas veterans of the Gulf War.

The reason the committee couldn’t compile a single case definition is that the studies in the literature do not report on key features of the illness including onset, duration, severity, frequency of symptoms, and exclusionary criteria. The Department of Veterans Affairs should boost efforts to collect these kinds of data, conduct earlier in-depth assessments after deployment when unexpected complaints occur, and track troops’ exposures to vaccinations, drugs, and environmental factors, the report recommends.

The name Gulf War illness won out over Gulf War syndrome because "syndrome" indicates a new group of signs and symptoms, while the types and patterns of symptoms in this illness commonly are seen with other illnesses. The committee rejected "chronic multisymptom illness" because the phrase is not specific to Gulf War veterans.

The committee included experts in clinical medicine, toxicology, psychiatry, neurology, gastroenterology, epidemiology, sociology, psychometrics, biostatistics, occupational medicine, and basic science.

The report does not include potential disclosures of conflicts of interest.

[email protected]

On Twitter @sherryboschert

An Institute of Medicine committee could not reach consensus on a single definition of Gulf War illness and recommended in a new report that clinicians and researchers at least narrow it down to two definitions.

That’s the preferred term – Gulf War illness – for a slew of health problems that occur at a higher rate in the approximately 697,000 U.S. veterans who served in the 1990-1991 Gulf War than in other veterans, the committee said. Gulf War illness is widely used and is more accurate than other terms used over the years for the same problems, including Gulf War syndrome, chronic multisystem illness, unexplained illness, medically unexplained symptoms, and medically unexplained physical symptoms, the report stated.

The Institute of Medicine (IOM) drafted a committee of 16 experts at the request of the Department of Veterans Affairs to try to develop a case definition for what's now called Gulf War illness in order to help standardize diagnosis, inclusion in research studies, and treatments. The committee's 120-page report, "Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined," is available on the IOM website.

Unable to find validation for one definition because of methodologic limitations in the studies, the committee recommended using either a broader definition from the Centers for Disease Control and Prevention (CDC) or a more restrictive one from studies of Kansas veterans, depending on the situation. Between the two of them, the definitions capture the most common symptoms of Gulf War illness and provide a framework for more focused research and treatment, the report said.

The committee found 2,033 articles in the literature focused on Gulf War illness symptoms and closely reviewed 718 of them. It found no objective diagnostic criteria but saw cumulative evidence that Gulf War illness is real. Fatigue, pain, and neurocognitive, gastrointestinal, respiratory, and/or dermatologic symptoms were reported with higher frequency in Gulf War veterans than in veterans of the same era who had not been deployed or were deployed elsewhere.

To identify the illness in a Gulf War veteran, the CDC definition requires one or more symptoms in at least two of the following categories: fatigue, pain, or mood and cognition. The Kansas definition requires symptoms in at least three of the following domains: fatigue or sleep, pain, neurologic or cognitive or mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms.

The CDC definition identified the illness in 29%-60% of Gulf War veterans, depending on the population studied. The Kansas definition identified the illness in 34% of Kansas veterans of the Gulf War.

The reason the committee couldn’t compile a single case definition is that the studies in the literature do not report on key features of the illness including onset, duration, severity, frequency of symptoms, and exclusionary criteria. The Department of Veterans Affairs should boost efforts to collect these kinds of data, conduct earlier in-depth assessments after deployment when unexpected complaints occur, and track troops’ exposures to vaccinations, drugs, and environmental factors, the report recommends.

The name Gulf War illness won out over Gulf War syndrome because "syndrome" indicates a new group of signs and symptoms, while the types and patterns of symptoms in this illness commonly are seen with other illnesses. The committee rejected "chronic multisymptom illness" because the phrase is not specific to Gulf War veterans.

The committee included experts in clinical medicine, toxicology, psychiatry, neurology, gastroenterology, epidemiology, sociology, psychometrics, biostatistics, occupational medicine, and basic science.

The report does not include potential disclosures of conflicts of interest.

[email protected]

On Twitter @sherryboschert

An Institute of Medicine committee could not reach consensus on a single definition of Gulf War illness and recommended in a new report that clinicians and researchers at least narrow it down to two definitions.

That’s the preferred term – Gulf War illness – for a slew of health problems that occur at a higher rate in the approximately 697,000 U.S. veterans who served in the 1990-1991 Gulf War than in other veterans, the committee said. Gulf War illness is widely used and is more accurate than other terms used over the years for the same problems, including Gulf War syndrome, chronic multisystem illness, unexplained illness, medically unexplained symptoms, and medically unexplained physical symptoms, the report stated.

The Institute of Medicine (IOM) drafted a committee of 16 experts at the request of the Department of Veterans Affairs to try to develop a case definition for what's now called Gulf War illness in order to help standardize diagnosis, inclusion in research studies, and treatments. The committee's 120-page report, "Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined," is available on the IOM website.

Unable to find validation for one definition because of methodologic limitations in the studies, the committee recommended using either a broader definition from the Centers for Disease Control and Prevention (CDC) or a more restrictive one from studies of Kansas veterans, depending on the situation. Between the two of them, the definitions capture the most common symptoms of Gulf War illness and provide a framework for more focused research and treatment, the report said.

The committee found 2,033 articles in the literature focused on Gulf War illness symptoms and closely reviewed 718 of them. It found no objective diagnostic criteria but saw cumulative evidence that Gulf War illness is real. Fatigue, pain, and neurocognitive, gastrointestinal, respiratory, and/or dermatologic symptoms were reported with higher frequency in Gulf War veterans than in veterans of the same era who had not been deployed or were deployed elsewhere.

To identify the illness in a Gulf War veteran, the CDC definition requires one or more symptoms in at least two of the following categories: fatigue, pain, or mood and cognition. The Kansas definition requires symptoms in at least three of the following domains: fatigue or sleep, pain, neurologic or cognitive or mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms.

The CDC definition identified the illness in 29%-60% of Gulf War veterans, depending on the population studied. The Kansas definition identified the illness in 34% of Kansas veterans of the Gulf War.

The reason the committee couldn’t compile a single case definition is that the studies in the literature do not report on key features of the illness including onset, duration, severity, frequency of symptoms, and exclusionary criteria. The Department of Veterans Affairs should boost efforts to collect these kinds of data, conduct earlier in-depth assessments after deployment when unexpected complaints occur, and track troops’ exposures to vaccinations, drugs, and environmental factors, the report recommends.

The name Gulf War illness won out over Gulf War syndrome because "syndrome" indicates a new group of signs and symptoms, while the types and patterns of symptoms in this illness commonly are seen with other illnesses. The committee rejected "chronic multisymptom illness" because the phrase is not specific to Gulf War veterans.

The committee included experts in clinical medicine, toxicology, psychiatry, neurology, gastroenterology, epidemiology, sociology, psychometrics, biostatistics, occupational medicine, and basic science.

The report does not include potential disclosures of conflicts of interest.

[email protected]

On Twitter @sherryboschert

Worker prepares capsules

for use in a clinical trial

Credit: Esther Dyson

Too many discontinued clinical trials go unreported to ethics committees and remain unpublished, according to a paper published in JAMA.

Investigators evaluated more than 1000 randomized clinical trials (RCTs) initiated in 3 countries between 2000 and 2003. And they found that roughly a quarter of these trials were ultimately discontinued.

Although all of these RCTs had been approved by research ethics committees, less than 40% of the discontinuations were reported to the committees.

And discontinued trials were significantly more likely than completed trials to remain unpublished.

The most common reason for discontinuation was insufficient subject enrollment.

Benjamin Kasenda, MD, of University Hospital Basel in Switzerland, and his colleagues conducted this research. They examined the characteristics of 1017 RCTs approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. The last follow-up of these trials was April 27, 2013.

Overall, 253 RCTs (24.9%) were discontinued, but only 38% of these discontinuations were reported to ethics committees.

Discontinued trials were more likely than completed trials to remain unpublished—55.1% vs 33.6% (P<0.001).

The most common reasons for discontinuation were poor recruitment (9.9%, 101/1017), administrative reasons (3.8%, 39/1017), and futility (3.6%, 37/1017).

A multivariate analysis revealed that industry sponsorship, compared to investigator sponsorship, and a larger planned sample size in increments of 100 were associated with lower rates of discontinuation due to poor recruitment. The adjusted odds ratios were 0.25 (P<0.001) and 0.96 (P=0.04), respectively.

Dr Kasenda and his colleagues said these results suggest researchers must put forth more effort to ensure that trial discontinuation is reported to ethics committees and that results of discontinued trials are published.

They said failure to publish these results is “a waste of valid data that could contribute to systematic reviews and meta-analyses.” In addition, taking steps to improve subject recruitment could greatly reduce RCT discontinuation.

Worker prepares capsules

for use in a clinical trial

Credit: Esther Dyson

Too many discontinued clinical trials go unreported to ethics committees and remain unpublished, according to a paper published in JAMA.

Investigators evaluated more than 1000 randomized clinical trials (RCTs) initiated in 3 countries between 2000 and 2003. And they found that roughly a quarter of these trials were ultimately discontinued.

Although all of these RCTs had been approved by research ethics committees, less than 40% of the discontinuations were reported to the committees.

And discontinued trials were significantly more likely than completed trials to remain unpublished.

The most common reason for discontinuation was insufficient subject enrollment.

Benjamin Kasenda, MD, of University Hospital Basel in Switzerland, and his colleagues conducted this research. They examined the characteristics of 1017 RCTs approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. The last follow-up of these trials was April 27, 2013.

Overall, 253 RCTs (24.9%) were discontinued, but only 38% of these discontinuations were reported to ethics committees.

Discontinued trials were more likely than completed trials to remain unpublished—55.1% vs 33.6% (P<0.001).

The most common reasons for discontinuation were poor recruitment (9.9%, 101/1017), administrative reasons (3.8%, 39/1017), and futility (3.6%, 37/1017).

A multivariate analysis revealed that industry sponsorship, compared to investigator sponsorship, and a larger planned sample size in increments of 100 were associated with lower rates of discontinuation due to poor recruitment. The adjusted odds ratios were 0.25 (P<0.001) and 0.96 (P=0.04), respectively.

Dr Kasenda and his colleagues said these results suggest researchers must put forth more effort to ensure that trial discontinuation is reported to ethics committees and that results of discontinued trials are published.

They said failure to publish these results is “a waste of valid data that could contribute to systematic reviews and meta-analyses.” In addition, taking steps to improve subject recruitment could greatly reduce RCT discontinuation.

Worker prepares capsules

for use in a clinical trial

Credit: Esther Dyson

Too many discontinued clinical trials go unreported to ethics committees and remain unpublished, according to a paper published in JAMA.

Investigators evaluated more than 1000 randomized clinical trials (RCTs) initiated in 3 countries between 2000 and 2003. And they found that roughly a quarter of these trials were ultimately discontinued.

Although all of these RCTs had been approved by research ethics committees, less than 40% of the discontinuations were reported to the committees.

And discontinued trials were significantly more likely than completed trials to remain unpublished.

The most common reason for discontinuation was insufficient subject enrollment.

Benjamin Kasenda, MD, of University Hospital Basel in Switzerland, and his colleagues conducted this research. They examined the characteristics of 1017 RCTs approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. The last follow-up of these trials was April 27, 2013.

Overall, 253 RCTs (24.9%) were discontinued, but only 38% of these discontinuations were reported to ethics committees.

Discontinued trials were more likely than completed trials to remain unpublished—55.1% vs 33.6% (P<0.001).

The most common reasons for discontinuation were poor recruitment (9.9%, 101/1017), administrative reasons (3.8%, 39/1017), and futility (3.6%, 37/1017).

A multivariate analysis revealed that industry sponsorship, compared to investigator sponsorship, and a larger planned sample size in increments of 100 were associated with lower rates of discontinuation due to poor recruitment. The adjusted odds ratios were 0.25 (P<0.001) and 0.96 (P=0.04), respectively.

Dr Kasenda and his colleagues said these results suggest researchers must put forth more effort to ensure that trial discontinuation is reported to ethics committees and that results of discontinued trials are published.

They said failure to publish these results is “a waste of valid data that could contribute to systematic reviews and meta-analyses.” In addition, taking steps to improve subject recruitment could greatly reduce RCT discontinuation.

GRAPEVINE, TEXAS—Adding specialized T cells to allogeneic bone marrow transplants can prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect, preclinical research suggests.

Donor-derived CD4+ invariant natural killer T cells (iNKT cells) helped protect mice from developing GVHD and lymphoma, thereby improving their survival.

As human CD4+ iNKT cells can be expanded in vitro, these findings may translate to the clinic, said study investigator Dominik Schneidawind, MD, of Stanford University in California.

Dr Schneidawind discussed this research at the 2014 BMT Tandem Meetings as abstract 2*, which was designated one of the meeting’s “Best Abstracts.”

Improved survival

Dr Schneidawind and his colleagues created a model of allogeneic bone marrow transplant in Balb/c (H-2Kd) mice. The mice were first irradiated with 8 Gy and then received T cell-depleted bone marrow, along with 1 x 10⁶ CD4/CD8 T cells (Tcon) from C57Bl/6 (H-2Kb) donor mice and varying doses of CD4+ iNKT cells: 1 x 10⁴ to 1 x 10⁵.

Mice that received 100,000 CD4+ iNKT cells had significantly improved survival (P=0.002)—and better weight and GVHD scores—compared to mice that received bone marrow grafts alone. But a CD4+ iNKT dose as low as 10,000 cells also conferred a significant improvement in survival (P=0.03).

“In contrast, you need roughly 500,000 to 1 million donor-derived regulatory T cells to achieve a comparable survival benefit in this model of bone marrow transplantation,” Dr Schneidawind noted.

GVT effect

Dr Schneidawind and his colleagues also evaluated the impact of CD4+ iNKT cells on the GVT effect. They used luciferase-transfected BCL1 cells to induce lymphoma development, injecting the cells into mice 1 day before transplant.

Mice that received BCL1 cells, with or without CD4+ iNKT cells, showed increasing bioluminescence imaging (BLI) signals and all died from progressive lymphoma. The mice that received BLC1 and Tcon did not show an increase in BLI signals, but they all died from GVHD.

However, the mice that received BCL1, Tcon, and CD4+ iNKT cells didn’t show any sign of lymphoma or GVHD and survived through the whole experiment (P=0.002).

The investigators conducted the same experiment with the luciferase-positive A20 cell line. And they observed similar results. Mice that received A20 cells, Tcon, and CD4+ iNKT cells showed no sign of lymphoma and had significantly improved survival (P=0.002) over animals that received A20 and Tcon.

“Interestingly, animals that received A20 cells and 50,000 CD4+ iNKT cells only, without Tcon, showed a significant decrease in BLI signal and significantly improved survival,” Dr Schneidawind noted.

“So we conclude from these experiments that CD4+ iNKT cells do not abrogate the Tcon-mediated [GVT] effect but might exert some distinct antitumor activity by themselves.”

Mechanism of GVHD prevention

Lastly, Dr Schneidawind and his colleagues wanted to determine exactly how CD4+ iNKT cells prevent GVHD. The group’s experiments showed that the cells inhibit the proliferation of alloreactive T cells and promote the expansion of donor-derived CD4+ FoxP3+ Tregs.

The investigators decided to take a closer look at the Tregs, evaluating their role in GVHD-related death.

To do this, the team evaluated survival in 4 groups of mice: (1) irradiated controls; (2) mice that received only bone marrow; (3) mice that received Tcon, CD4+ iNKT cells, and a graft depleted of CD4+ FoxP3+ Tregs; and (4) mice that received Tcon, CD4+ iNKT cells, and a non-depleted graft.

“Animals that received a Treg-depleted graft and were treated with CD4+ iNKT [plus Tcon] did not show a significant improvement in survival [over controls],” Dr Schneidawind said.

“In contrast, animals that received a Treg-non-depleted graft showed a significant improvement in survival [P=0.006]. So we conclude that the expansion of these Tregs is necessary to protect from GVHD lethality and that they are required in this context.”

In closing, Dr Schneidawind noted that, although human CD4+ iNKT cells are rare, they can be isolated from peripheral blood and expanded in vitro. This suggests his group’s findings might ultimately prove useful for patients.

*Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—Adding specialized T cells to allogeneic bone marrow transplants can prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect, preclinical research suggests.

Donor-derived CD4+ invariant natural killer T cells (iNKT cells) helped protect mice from developing GVHD and lymphoma, thereby improving their survival.

As human CD4+ iNKT cells can be expanded in vitro, these findings may translate to the clinic, said study investigator Dominik Schneidawind, MD, of Stanford University in California.

Dr Schneidawind discussed this research at the 2014 BMT Tandem Meetings as abstract 2*, which was designated one of the meeting’s “Best Abstracts.”

Improved survival

Dr Schneidawind and his colleagues created a model of allogeneic bone marrow transplant in Balb/c (H-2Kd) mice. The mice were first irradiated with 8 Gy and then received T cell-depleted bone marrow, along with 1 x 10⁶ CD4/CD8 T cells (Tcon) from C57Bl/6 (H-2Kb) donor mice and varying doses of CD4+ iNKT cells: 1 x 10⁴ to 1 x 10⁵.

Mice that received 100,000 CD4+ iNKT cells had significantly improved survival (P=0.002)—and better weight and GVHD scores—compared to mice that received bone marrow grafts alone. But a CD4+ iNKT dose as low as 10,000 cells also conferred a significant improvement in survival (P=0.03).

“In contrast, you need roughly 500,000 to 1 million donor-derived regulatory T cells to achieve a comparable survival benefit in this model of bone marrow transplantation,” Dr Schneidawind noted.

GVT effect

Dr Schneidawind and his colleagues also evaluated the impact of CD4+ iNKT cells on the GVT effect. They used luciferase-transfected BCL1 cells to induce lymphoma development, injecting the cells into mice 1 day before transplant.

Mice that received BCL1 cells, with or without CD4+ iNKT cells, showed increasing bioluminescence imaging (BLI) signals and all died from progressive lymphoma. The mice that received BLC1 and Tcon did not show an increase in BLI signals, but they all died from GVHD.

However, the mice that received BCL1, Tcon, and CD4+ iNKT cells didn’t show any sign of lymphoma or GVHD and survived through the whole experiment (P=0.002).

The investigators conducted the same experiment with the luciferase-positive A20 cell line. And they observed similar results. Mice that received A20 cells, Tcon, and CD4+ iNKT cells showed no sign of lymphoma and had significantly improved survival (P=0.002) over animals that received A20 and Tcon.

“Interestingly, animals that received A20 cells and 50,000 CD4+ iNKT cells only, without Tcon, showed a significant decrease in BLI signal and significantly improved survival,” Dr Schneidawind noted.

“So we conclude from these experiments that CD4+ iNKT cells do not abrogate the Tcon-mediated [GVT] effect but might exert some distinct antitumor activity by themselves.”

Mechanism of GVHD prevention

Lastly, Dr Schneidawind and his colleagues wanted to determine exactly how CD4+ iNKT cells prevent GVHD. The group’s experiments showed that the cells inhibit the proliferation of alloreactive T cells and promote the expansion of donor-derived CD4+ FoxP3+ Tregs.

The investigators decided to take a closer look at the Tregs, evaluating their role in GVHD-related death.

To do this, the team evaluated survival in 4 groups of mice: (1) irradiated controls; (2) mice that received only bone marrow; (3) mice that received Tcon, CD4+ iNKT cells, and a graft depleted of CD4+ FoxP3+ Tregs; and (4) mice that received Tcon, CD4+ iNKT cells, and a non-depleted graft.

“Animals that received a Treg-depleted graft and were treated with CD4+ iNKT [plus Tcon] did not show a significant improvement in survival [over controls],” Dr Schneidawind said.

“In contrast, animals that received a Treg-non-depleted graft showed a significant improvement in survival [P=0.006]. So we conclude that the expansion of these Tregs is necessary to protect from GVHD lethality and that they are required in this context.”

In closing, Dr Schneidawind noted that, although human CD4+ iNKT cells are rare, they can be isolated from peripheral blood and expanded in vitro. This suggests his group’s findings might ultimately prove useful for patients.

*Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—Adding specialized T cells to allogeneic bone marrow transplants can prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect, preclinical research suggests.

Donor-derived CD4+ invariant natural killer T cells (iNKT cells) helped protect mice from developing GVHD and lymphoma, thereby improving their survival.

As human CD4+ iNKT cells can be expanded in vitro, these findings may translate to the clinic, said study investigator Dominik Schneidawind, MD, of Stanford University in California.

Dr Schneidawind discussed this research at the 2014 BMT Tandem Meetings as abstract 2*, which was designated one of the meeting’s “Best Abstracts.”

Improved survival

Dr Schneidawind and his colleagues created a model of allogeneic bone marrow transplant in Balb/c (H-2Kd) mice. The mice were first irradiated with 8 Gy and then received T cell-depleted bone marrow, along with 1 x 10⁶ CD4/CD8 T cells (Tcon) from C57Bl/6 (H-2Kb) donor mice and varying doses of CD4+ iNKT cells: 1 x 10⁴ to 1 x 10⁵.

Mice that received 100,000 CD4+ iNKT cells had significantly improved survival (P=0.002)—and better weight and GVHD scores—compared to mice that received bone marrow grafts alone. But a CD4+ iNKT dose as low as 10,000 cells also conferred a significant improvement in survival (P=0.03).

“In contrast, you need roughly 500,000 to 1 million donor-derived regulatory T cells to achieve a comparable survival benefit in this model of bone marrow transplantation,” Dr Schneidawind noted.

GVT effect

Dr Schneidawind and his colleagues also evaluated the impact of CD4+ iNKT cells on the GVT effect. They used luciferase-transfected BCL1 cells to induce lymphoma development, injecting the cells into mice 1 day before transplant.

Mice that received BCL1 cells, with or without CD4+ iNKT cells, showed increasing bioluminescence imaging (BLI) signals and all died from progressive lymphoma. The mice that received BLC1 and Tcon did not show an increase in BLI signals, but they all died from GVHD.

However, the mice that received BCL1, Tcon, and CD4+ iNKT cells didn’t show any sign of lymphoma or GVHD and survived through the whole experiment (P=0.002).

The investigators conducted the same experiment with the luciferase-positive A20 cell line. And they observed similar results. Mice that received A20 cells, Tcon, and CD4+ iNKT cells showed no sign of lymphoma and had significantly improved survival (P=0.002) over animals that received A20 and Tcon.

“Interestingly, animals that received A20 cells and 50,000 CD4+ iNKT cells only, without Tcon, showed a significant decrease in BLI signal and significantly improved survival,” Dr Schneidawind noted.

“So we conclude from these experiments that CD4+ iNKT cells do not abrogate the Tcon-mediated [GVT] effect but might exert some distinct antitumor activity by themselves.”

Mechanism of GVHD prevention

Lastly, Dr Schneidawind and his colleagues wanted to determine exactly how CD4+ iNKT cells prevent GVHD. The group’s experiments showed that the cells inhibit the proliferation of alloreactive T cells and promote the expansion of donor-derived CD4+ FoxP3+ Tregs.

The investigators decided to take a closer look at the Tregs, evaluating their role in GVHD-related death.

To do this, the team evaluated survival in 4 groups of mice: (1) irradiated controls; (2) mice that received only bone marrow; (3) mice that received Tcon, CD4+ iNKT cells, and a graft depleted of CD4+ FoxP3+ Tregs; and (4) mice that received Tcon, CD4+ iNKT cells, and a non-depleted graft.

“Animals that received a Treg-depleted graft and were treated with CD4+ iNKT [plus Tcon] did not show a significant improvement in survival [over controls],” Dr Schneidawind said.

“In contrast, animals that received a Treg-non-depleted graft showed a significant improvement in survival [P=0.006]. So we conclude that the expansion of these Tregs is necessary to protect from GVHD lethality and that they are required in this context.”

In closing, Dr Schneidawind noted that, although human CD4+ iNKT cells are rare, they can be isolated from peripheral blood and expanded in vitro. This suggests his group’s findings might ultimately prove useful for patients.

*Information in the abstract differs from that presented.

Science journals

Credit: CDC/James Gathany

New research has revealed discrepancies between information posted on the ClinicalTrials.gov website and information published in journals.

During a 1-year period, nearly all of the trials published in “high-impact” journals and listed on ClinicalTrials.gov had at least 1 discrepancy between the 2 sources.

This included differences in study group data, intervention information, and primary and secondary endpoints.

Jessica E. Becker, of the Yale University School of Medicine in New Haven, Connecticut, and her colleagues disclosed these findings in a letter to JAMA.

The researchers identified 96 trials reporting results on ClinicalTrials.gov that were also published in 19 “high-impact” journals from July 1, 2010, to June 30, 2011. The trials were most frequently published in NEJM (n=23; 24%), The Lancet (n=18; 19%), and JAMA (n=11; 12%).

Common conditions investigated in these studies included cardiovascular disease, diabetes, and hyperlipidemia (n=21; 23%); cancer (n=20; 21%); and infectious disease (n=19; 20%). Seventy-three percent of the trials (n=70) were primarily funded by industry.

Cohort, intervention, and efficacy endpoint information was reported in both the journal and on ClinicalTrials.gov for most of the trials—ranging from 93% to 100%.

For 97% of the trials (93/96), there was at least 1 difference in information between the registry and the journal article. The level of discordance between the sources was lowest for enrollment numbers—2%—and highest for completion rates—22%.

Discordance was also quite high for the trial interventions (16%). This included differences in dosage descriptions, frequencies, and duration of the intervention.

There were 132 primary efficacy endpoints described in both sources. Fifty-two percent of these endpoints could be compared between the 2 sources and had concordant results. Results for 23% (n=30) could not be compared, and 16% (n=21) were discordant.

The majority (n=15) of discordant results did not alter the interpretation of the trial. But for 6 trials, the discordance did affect interpretation.

These trials had differences in time to disease progression, rate of disease recurrence, time to resolution of a condition, progression-free survival, and results of statistical analyses.

Among the 619 secondary efficacy endpoints that were described in both sources, results for 37% (n=228) could not be compared, and 9% (n=53) were discordant. Overall, 16% of secondary efficacy endpoints were described in both sources and reported concordant results.

The researchers said this study raises questions about the accuracy of information published on ClinicalTrials.gov and in journals.

Furthermore, because the journals studied have rigorous peer review processes, the trials in this sample may represent best-case scenarios with regard to the quality of results reporting.

Science journals

Credit: CDC/James Gathany

New research has revealed discrepancies between information posted on the ClinicalTrials.gov website and information published in journals.

During a 1-year period, nearly all of the trials published in “high-impact” journals and listed on ClinicalTrials.gov had at least 1 discrepancy between the 2 sources.

This included differences in study group data, intervention information, and primary and secondary endpoints.

Jessica E. Becker, of the Yale University School of Medicine in New Haven, Connecticut, and her colleagues disclosed these findings in a letter to JAMA.

The researchers identified 96 trials reporting results on ClinicalTrials.gov that were also published in 19 “high-impact” journals from July 1, 2010, to June 30, 2011. The trials were most frequently published in NEJM (n=23; 24%), The Lancet (n=18; 19%), and JAMA (n=11; 12%).

Common conditions investigated in these studies included cardiovascular disease, diabetes, and hyperlipidemia (n=21; 23%); cancer (n=20; 21%); and infectious disease (n=19; 20%). Seventy-three percent of the trials (n=70) were primarily funded by industry.

Cohort, intervention, and efficacy endpoint information was reported in both the journal and on ClinicalTrials.gov for most of the trials—ranging from 93% to 100%.

For 97% of the trials (93/96), there was at least 1 difference in information between the registry and the journal article. The level of discordance between the sources was lowest for enrollment numbers—2%—and highest for completion rates—22%.

Discordance was also quite high for the trial interventions (16%). This included differences in dosage descriptions, frequencies, and duration of the intervention.

There were 132 primary efficacy endpoints described in both sources. Fifty-two percent of these endpoints could be compared between the 2 sources and had concordant results. Results for 23% (n=30) could not be compared, and 16% (n=21) were discordant.

The majority (n=15) of discordant results did not alter the interpretation of the trial. But for 6 trials, the discordance did affect interpretation.

These trials had differences in time to disease progression, rate of disease recurrence, time to resolution of a condition, progression-free survival, and results of statistical analyses.

Among the 619 secondary efficacy endpoints that were described in both sources, results for 37% (n=228) could not be compared, and 9% (n=53) were discordant. Overall, 16% of secondary efficacy endpoints were described in both sources and reported concordant results.

The researchers said this study raises questions about the accuracy of information published on ClinicalTrials.gov and in journals.

Furthermore, because the journals studied have rigorous peer review processes, the trials in this sample may represent best-case scenarios with regard to the quality of results reporting.

Science journals

Credit: CDC/James Gathany

New research has revealed discrepancies between information posted on the ClinicalTrials.gov website and information published in journals.

During a 1-year period, nearly all of the trials published in “high-impact” journals and listed on ClinicalTrials.gov had at least 1 discrepancy between the 2 sources.

This included differences in study group data, intervention information, and primary and secondary endpoints.

Jessica E. Becker, of the Yale University School of Medicine in New Haven, Connecticut, and her colleagues disclosed these findings in a letter to JAMA.

The researchers identified 96 trials reporting results on ClinicalTrials.gov that were also published in 19 “high-impact” journals from July 1, 2010, to June 30, 2011. The trials were most frequently published in NEJM (n=23; 24%), The Lancet (n=18; 19%), and JAMA (n=11; 12%).

Common conditions investigated in these studies included cardiovascular disease, diabetes, and hyperlipidemia (n=21; 23%); cancer (n=20; 21%); and infectious disease (n=19; 20%). Seventy-three percent of the trials (n=70) were primarily funded by industry.

Cohort, intervention, and efficacy endpoint information was reported in both the journal and on ClinicalTrials.gov for most of the trials—ranging from 93% to 100%.

For 97% of the trials (93/96), there was at least 1 difference in information between the registry and the journal article. The level of discordance between the sources was lowest for enrollment numbers—2%—and highest for completion rates—22%.

Discordance was also quite high for the trial interventions (16%). This included differences in dosage descriptions, frequencies, and duration of the intervention.

There were 132 primary efficacy endpoints described in both sources. Fifty-two percent of these endpoints could be compared between the 2 sources and had concordant results. Results for 23% (n=30) could not be compared, and 16% (n=21) were discordant.

The majority (n=15) of discordant results did not alter the interpretation of the trial. But for 6 trials, the discordance did affect interpretation.

These trials had differences in time to disease progression, rate of disease recurrence, time to resolution of a condition, progression-free survival, and results of statistical analyses.

Among the 619 secondary efficacy endpoints that were described in both sources, results for 37% (n=228) could not be compared, and 9% (n=53) were discordant. Overall, 16% of secondary efficacy endpoints were described in both sources and reported concordant results.

The researchers said this study raises questions about the accuracy of information published on ClinicalTrials.gov and in journals.

Furthermore, because the journals studied have rigorous peer review processes, the trials in this sample may represent best-case scenarios with regard to the quality of results reporting.

This month in our issue, we look at the challenges and rewards of global health work. Hospitalist Dr. Brett Hendel-Paterson, who participates in HealthPartners’ Travel and Tropical Medicine Center in St. Paul, Minnesota discusses how humility, curiosity, and hope are at the root of clinicians’ experiences in global health work, and the long-term commitment and social contract needed to do the job. Dr. Evan Lyon, head of the University of Chicago’s Global Hospital Medicine Fellowship program, shares how global health work has influenced his interactions with his patients.

For those attending the Society of Hospital Medicine’s annual conference, HM14, we offer tips on using the HM14 In Hand mobile app to navigate the courses, events, and must-sees at this year’s convention.

Also in this issue, we look at what makes a hospital medicine group effective, offer Dr. Win Whitcomb’s primer on the relative value unit and its place in the shift from volume-to-value reimbursement, look at CMS’s efforts to increase participation in the physician quality reporting system, and our Key Clinical Question covers which patients undergoing gastrointestinal endoscopic procedures should receive antibiotic prophylaxis.

Click here to listen to the March highlights podcast.

This month in our issue, we look at the challenges and rewards of global health work. Hospitalist Dr. Brett Hendel-Paterson, who participates in HealthPartners’ Travel and Tropical Medicine Center in St. Paul, Minnesota discusses how humility, curiosity, and hope are at the root of clinicians’ experiences in global health work, and the long-term commitment and social contract needed to do the job. Dr. Evan Lyon, head of the University of Chicago’s Global Hospital Medicine Fellowship program, shares how global health work has influenced his interactions with his patients.

For those attending the Society of Hospital Medicine’s annual conference, HM14, we offer tips on using the HM14 In Hand mobile app to navigate the courses, events, and must-sees at this year’s convention.

Also in this issue, we look at what makes a hospital medicine group effective, offer Dr. Win Whitcomb’s primer on the relative value unit and its place in the shift from volume-to-value reimbursement, look at CMS’s efforts to increase participation in the physician quality reporting system, and our Key Clinical Question covers which patients undergoing gastrointestinal endoscopic procedures should receive antibiotic prophylaxis.

Click here to listen to the March highlights podcast.

This month in our issue, we look at the challenges and rewards of global health work. Hospitalist Dr. Brett Hendel-Paterson, who participates in HealthPartners’ Travel and Tropical Medicine Center in St. Paul, Minnesota discusses how humility, curiosity, and hope are at the root of clinicians’ experiences in global health work, and the long-term commitment and social contract needed to do the job. Dr. Evan Lyon, head of the University of Chicago’s Global Hospital Medicine Fellowship program, shares how global health work has influenced his interactions with his patients.

For those attending the Society of Hospital Medicine’s annual conference, HM14, we offer tips on using the HM14 In Hand mobile app to navigate the courses, events, and must-sees at this year’s convention.

Also in this issue, we look at what makes a hospital medicine group effective, offer Dr. Win Whitcomb’s primer on the relative value unit and its place in the shift from volume-to-value reimbursement, look at CMS’s efforts to increase participation in the physician quality reporting system, and our Key Clinical Question covers which patients undergoing gastrointestinal endoscopic procedures should receive antibiotic prophylaxis.

Click here to listen to the March highlights podcast.

Listen to more of Dr. Lyon’s thoughts on rational testing and social context.

Listen to more of Dr. Lyon’s thoughts on rational testing and social context.

Listen to more of Dr. Lyon’s thoughts on rational testing and social context.

Hospitalist Vincent DeGennaro, Jr., MD, MPH, didn’t train as an oncologist. But during the course of his daily duties at the Hospital Bernard Mevs in Port-au-Prince, Haiti, he administers chemotherapy at the hospital’s women’s cancer center.

“Chemotherapy was outside the realm of my specialty, but under the training and remote consultation of U.S. oncologists, I have become more comfortable with it,” says Dr. DeGennaro, an assistant professor in the division of hospital medicine at the University of Florida College of Medicine in Gainesville. Along with performing echocardiograms and working in Haiti’s only ICU, it’s an example of how global health forces him to be a “true generalist.” That’s also true of hospital medicine. In fact, the flexible schedule hospital medicine offers was a deciding factor in his career choice. Shift work in a discrete time period would allow him, he reasoned, to also follow his passion of global health.

Volunteering in low-resource settings was something that “felt right to me from the beginning,” Dr. DeGennaro says. He worked in Honduras and the Dominican Republic during medical school, mostly through medical missions organizations. Work with Partners in Health during medical school and in Rwanda after residency exposed him to the capacity-building goals of that organization. He now spends seven months of the academic year in Haiti, where he is helping Project Medishare (www.projectmedishare.org) in its efforts to build capacity and infrastructure at the country’s major trauma hospital. In July, he will be supervising clinical fellows as the director of the University of Florida’s first HM global health fellowship program.

Haitian patients have to pay for their own tests, so Dr. DeGennaro must carefully choose those that will guide his management decisions for patients. “Low-resource utilization forces you to become a better clinician,” he says. “I think we have gotten intellectually lazy in the United States, where we can order a dozen tests and let the results guide us instead of using our clinical skills to narrow what tests to order.”

Delivering care in under-resourced countries, he adds, has changed him: “I’m a much better doctor for it.”

Gretchen Henkel is a freelance writer in California.

Hospitalist Vincent DeGennaro, Jr., MD, MPH, didn’t train as an oncologist. But during the course of his daily duties at the Hospital Bernard Mevs in Port-au-Prince, Haiti, he administers chemotherapy at the hospital’s women’s cancer center.

“Chemotherapy was outside the realm of my specialty, but under the training and remote consultation of U.S. oncologists, I have become more comfortable with it,” says Dr. DeGennaro, an assistant professor in the division of hospital medicine at the University of Florida College of Medicine in Gainesville. Along with performing echocardiograms and working in Haiti’s only ICU, it’s an example of how global health forces him to be a “true generalist.” That’s also true of hospital medicine. In fact, the flexible schedule hospital medicine offers was a deciding factor in his career choice. Shift work in a discrete time period would allow him, he reasoned, to also follow his passion of global health.

Volunteering in low-resource settings was something that “felt right to me from the beginning,” Dr. DeGennaro says. He worked in Honduras and the Dominican Republic during medical school, mostly through medical missions organizations. Work with Partners in Health during medical school and in Rwanda after residency exposed him to the capacity-building goals of that organization. He now spends seven months of the academic year in Haiti, where he is helping Project Medishare (www.projectmedishare.org) in its efforts to build capacity and infrastructure at the country’s major trauma hospital. In July, he will be supervising clinical fellows as the director of the University of Florida’s first HM global health fellowship program.

Haitian patients have to pay for their own tests, so Dr. DeGennaro must carefully choose those that will guide his management decisions for patients. “Low-resource utilization forces you to become a better clinician,” he says. “I think we have gotten intellectually lazy in the United States, where we can order a dozen tests and let the results guide us instead of using our clinical skills to narrow what tests to order.”

Delivering care in under-resourced countries, he adds, has changed him: “I’m a much better doctor for it.”

Gretchen Henkel is a freelance writer in California.

Hospitalist Vincent DeGennaro, Jr., MD, MPH, didn’t train as an oncologist. But during the course of his daily duties at the Hospital Bernard Mevs in Port-au-Prince, Haiti, he administers chemotherapy at the hospital’s women’s cancer center.

“Chemotherapy was outside the realm of my specialty, but under the training and remote consultation of U.S. oncologists, I have become more comfortable with it,” says Dr. DeGennaro, an assistant professor in the division of hospital medicine at the University of Florida College of Medicine in Gainesville. Along with performing echocardiograms and working in Haiti’s only ICU, it’s an example of how global health forces him to be a “true generalist.” That’s also true of hospital medicine. In fact, the flexible schedule hospital medicine offers was a deciding factor in his career choice. Shift work in a discrete time period would allow him, he reasoned, to also follow his passion of global health.

Volunteering in low-resource settings was something that “felt right to me from the beginning,” Dr. DeGennaro says. He worked in Honduras and the Dominican Republic during medical school, mostly through medical missions organizations. Work with Partners in Health during medical school and in Rwanda after residency exposed him to the capacity-building goals of that organization. He now spends seven months of the academic year in Haiti, where he is helping Project Medishare (www.projectmedishare.org) in its efforts to build capacity and infrastructure at the country’s major trauma hospital. In July, he will be supervising clinical fellows as the director of the University of Florida’s first HM global health fellowship program.

Haitian patients have to pay for their own tests, so Dr. DeGennaro must carefully choose those that will guide his management decisions for patients. “Low-resource utilization forces you to become a better clinician,” he says. “I think we have gotten intellectually lazy in the United States, where we can order a dozen tests and let the results guide us instead of using our clinical skills to narrow what tests to order.”

Delivering care in under-resourced countries, he adds, has changed him: “I’m a much better doctor for it.”

Gretchen Henkel is a freelance writer in California.